Peripheral neuropathy usually presents with weakness and sensory loss or pain in the arms and legs. It is estimated that 10% to 22% of people in the United States suffer from neuropathy, the incidence of which increases with age. Neuropathies are classified according to cause (endocrine, metabolic, nutritional, toxic, etc) or clinical presentation (sensory, motor, autonomic, mixed sensory and motor, mononeuritis, mononeuritis multiplex, etc). Due to the diverse causes of neuropathy, laboratory testing is invariably required for diagnosis or etiologic identification.

The following is a brief review of the known causes of acquired peripheral neuropathies and the laboratory tests available for their evaluation and diagnosis. The Table is provided for informational purposes only and is not intended as medical advice. A physician's test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

Endocrine causes of neuropathy
include diabetes mellitus and hypothyroidism. The most common cause of
neuropathy is diabetes mellitus, which accounts for approximately 30% of
cases. Approximately 50% of individuals with diabetes will develop neuropathy,
and in some cases, neuropathy is the presenting complaint. The most frequent
presentation is distal sensory polyneuropathy, but patients may also present
with small fiber neuropathy (commonly caused by glucose intolerance),
sensorimotor neuropathy, amyotrophy, mononeuritis, or mononeuritis multiplex.
Diagnostic tests for diabetes mellitus include glycated hemoglobin (ie,
hemoglobin A1c), blood glucose, and glucose tolerance assays. Hemoglobin A1c
is also useful for monitoring diabetic control. Hypothyroidism presents
predominantly as a sensory neuropathy and can be diagnosed with thyroid
function tests including TSH and T4.

Metabolic causes of neuropathy
include renal failure and porphyria. Renal failure, indicated by elevated
serum creatinine and BUN, is associated with a predominantly sensory axonal
neuropathy. Porphyria is associated with an acute, predominantly motor,
neuropathy and is detected by urine porphyrin analysis.

Vitamin deficiency (B1,
B6, B12,
and E) and folate deficiency, as well as excessive intake of vitamin B6, can
cause peripheral neuropathy. B12 deficiency is associated with achlorhydria or pernicious anemia and sometimes
with parietal cell or intrinsic factor antibodies. Vitamin E deficiency
is often associated with ataxia. Measurement of serum vitamin levels is useful
in making the diagnosis.

Peripheral neuropathy may also be
caused by several heavy metals. Lead toxicity is associated with motor
neuropathy, whereas arsenic and mercury cause sensory neuropathy. The 24-hour
urine heavy metal test is the most useful test for diagnosis of heavy metal
toxicity.

The immune system mediates
peripheral neuropathies in autoimmune diseases, in systemic diseases such as
vasculitis and primary amyloidosis, and in paraneoplastic syndromes.
Autoimmune neuropathies are usually divided into Guillain-Barre syndrome,
variants that are of acute onset and self-limiting, and variants that are
chronic and follow a progressive or relapsing course. Glycoconjugate antigens,
both glycoproteins and glycolipids, have been identified as putative targets
for many of these autoimmune polyneuropathies. In general, IgG
glycoconjugate autoantibodies have been associated with acute
neuropathies, whereas IgM autoantibodies are associated with the chronic
neuropathic syndromes.

Acute immune-mediated neuropathies include the Guillain-Barre syndrome (GBS;
acute inflammatory demyelinating polyneuropathy), acute motor axonal
polyneuropathy, acute sensory polyneuropathy, acute autonomic polyneuropathy,
and the Miller-Fisher syndrome in which the extra-ocular muscles are affected.
Increased titers of IgG GM1 or GD1a ganglioside antibodies have been
associated with GBS and acute motor axonal neuropathy, whereas increased IgG GQ1b ganglioside antibodies are closely associated with the Miller-Fisher
syndrome. Tests for these autoantibodies are useful aids in the evaluation of
patients suspected of having these syndromes.

Chronic immune-mediated polyneuropathies in which the peripheral nerves are
selectively affected include chronic inflammatory demyelinating polyneuropathy
(CIDP), demyelinating polyneuropathy associated with IgM MAG
(myelin-associated glycoprotein) antibodies or SGPG (sulfoglucuronyl
paragloboside) antibodies, multifocal motor neuropathy associated with IgM
GM1 or GD1a antibodies, and sensory polyneuropathy associated with IgM
sulfatide antibodies or GD1b or disialosyl ganglioside antibodies.
Other neuropathies may be associated with GM2 antibodies. The presence of
increased titers of these autoantibodies helps diagnose an immune-mediated
polyneuropathy that may respond to specific immunotherapy. Some of these
autoantibodies also occur as IgM monoclonal gammopathies in patients with
non-malignant monoclonal gammopathies or in association with B-cell
lymphoproliferative disorders (see
paraneoplastic syndromes below).

Peripheral neuropathy can also occur in patients with rheumatologic diseases or systemic vasculitis, including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, and granulomatosis with polyangiitis (GPA; Wegener). SLE can be diagnosed with the aid of tests for anti-nuclear antibodies (ANA). SS-A/Ro and SS-B/La antibodies are consistent with Sjögren syndrome, and rheumatoid factor and cyclic citrullinated peptide antibody are consistent with rheumatoid arthritis. Anti-neutrophil cytoplasmic antibodies (ANCA), myeloperoxidase (MPO) antibody, and proteinase 3 (PR3) antibody are helpful for diagnosing GPA. Polyarteritis nodosa is another disease that is associated with vasculitis of the peripheral nerves, sometimes associated with hepatitis B. Chronic hepatitis C virus infection is associated with cryoglobulinemia, in which deposition of cryoglobulin-containing immune complexes causes small- and medium-size vessel disease. Vasculitis can also result from viral infections such as parvovirus. In viral infections, circulating immune complexes, cryoglobulins, or decreased complement levels (CH50) may be present. Vasculitic neuropathies typically present as mononeuritis, mononeuritis multiplex, or polyneuritis. However, Sjögren syndrome sometimes presents with sensory neuropathy or ganglioneuritis. Ribosomal P antibody may be present in these individuals. Celiac disease, an inflammatory disease of the gut that results from gluten intolerance, may be associated with a sensory neuropathy, sometimes with ganglioside antibodies. It can be recognized by the presence of gliadin, transglutaminase, or endomysial antibodies. Endomysial antibodies commonly, but not always, react with transglutaminase.

Other neuropathies that are, in part, mediated by the immune system are those
associated with neoplasia, monoclonal gammopathies, and primary amyloidosis
(see
below).

Symptoms of autoimmune encephalitis
include seizures; changes in memory, behavior, and cognition; and psychosis.
These encephalopathies may be caused by antibodies to neurotransmitter
receptors such as N-methyl-D-aspartate receptor 1 (NMDAR1), glutamate
receptors AMPAR1 and AMPAR2, and GABAB receptors. Encephalitis may also be
caused by antibodies to proteins within the voltage-gated potassium channel (VGKC)
complex such as leucine-rich glioma inactivated 1 (LGI1) and contactin-associated
protein 2 (CASPR2). Some cases of autoimmune encephalitis have been associated
with neoplasms such as teratomas.

Paraneoplastic syndromes are
thought to be caused by indirect effects of tumors, usually via immune or
metabolic mechanisms. Several paraneoplastic neuropathic syndromes have been
recognized. One of these is a predominantly sensory neuropathy that occurs in
patients with carcinoma of the lung in association with Hu antibodies,
which serve as a marker for the disease. Neuropathy is also associated with
IgM monoclonal gammopathies in patients with Waldenstrom macroglobulinemia or
B-cell leukemia or lymphoma and with IgG or IgA monoclonal gammopathies in
myeloma. The monoclonal IgMs in patients with neuropathy frequently exhibit
reactivity to one of the glycoconjugate antigens in peripheral nerves (see
above). In myeloma, the monoclonal IgG or IgA antibodies do not have
demonstrable autoantibody activity. Monoclonal gammopathy of any isotype, or
light chain disease, can also be associated with primary amyloidosis in which
the amyloid deposits contain fragments of the monoclonal light chains. The
same neuropathic syndromes can also be associated with non-malignant IgM, IgG,
or IgA monoclonal gammopathies, or monoclonal gammopathies of unknown
significance (MGUS). Laboratory tests that are useful for detecting monoclonal
gammopathies include an immunoglobulin profile (IgA, IgG, IgM) and
immunofixation electrophoresis of serum and urine. Measurement of free kappa
and free lambda light chain is useful for detecting light chain disease.